You are in: eMedicine Specialties > Dermatology > ALLERGY AND IMMUNOLOGY Fixed Drug EruptionsArticle Last Updated: Nov 15, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic David F Butler is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa Coauthor(s): Jordan R Ilse, MD, Staff Physician, Scott and White Internal Medicine Residency Program, Temple, Texas Editors: Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System Author and Editor Disclosure Synonyms and related keywords: fixed drug reaction, FDE, adverse drug reaction, adverse cutaneous drug reaction, drug-induced hypersensitivity, drug-induced pigmentation, postinflammatory hyperpigmentation, post-inflammatory hyperpigmentation INTRODUCTIONSection 2 of 11
  BackgroundAdverse reactions to medications are common and often manifest as a cutaneous eruption.
PathophysiologyAlthough the exact mechanism is unknown, recent research suggests a cell-mediated process that initiates both the active and quiescent lesions. The process may involve an antibody-dependent, cell-mediated cytotoxic response.4 Changes in cell surface markers allow vascular endothelium to select CD4 cells for migration into active lesions. These regulatory CD4 cells likely produce interleukin 10, which has been shown to help suppress immune function, resulting in a resting lesion.4 As the inflammatory response dissipates, interleukin 15 expression from keratinocytes is thought to help ensure the survival of CD8 cells, helping them fulfill their effector memory phenotypes. Thus, when reexposure to the drug occurs, a more rapid response develops in the exact location of any prior lesions.4 FrequencyUnited StatesThe prevalence of drug eruptions has been reported to range from 2-5% for inpatients and greater than 1% for outpatients.9 FDEs may account for as much as 16-21% of all cutaneous drug eruptions. The actual frequency may be higher than current estimates, owing to the availability of a variety of over-the-counter medications and nutritional supplements that are known to elicit FDEs. InternationalThe international prevalence is variable but is likely similar to that in the United States. Most studies report FDEs to be the second or third most common skin manifestation of adverse drug events.10 Mortality/MorbidityNo deaths have been attributed to FDEs. Widespread lesions may initially mimic toxic epidermal necrolysis, but they have a benign clinical course.11 Localized hyperpigmentation is a common complication, but pain, infection, and, rarely, hypopigmentation, also may occur.1 RaceFDEs have no known racial predilection. A genetic susceptibility to developing an FDE with an increased incidence of HLA-B22 is possible.12, 13 SexOne large study of 450 patients revealed a male-to-female ratio of 1:1.1.1 AgeFDEs have been reported in patients as young as 1.5 years and as old as 87 years. The mean age at presentation is 30.4 years in males and 31.3 years in females.1 CLINICALSection 3 of 11
HistoryThe initial eruption is often solitary and located on the sacral region, hip, proximal extremity, lip/perioral region, or genitalia. With the initial FDE attack, a delay of up to 2 weeks may occur from the initial exposure to the drug to the development of the skin lesion.14 Skin lesions develop over a period of hours but require days to become necrotic. Lesions may persist from days to weeks and then fade slowly to residual oval hyperpigmented patches.
Further questioning may reveal prior episodes of FDE, atopic disease, or other past drug reactions. Family history may render a history of atopy, drug reactions, or diabetes mellitus.1 PhysicalThe most common clinical manifestation is the pigmenting FDE, which usually manifests as round or oval, sharply demarcated erythematous/edematous plaques located on the lip, hip, sacrum, or genitalia.2 These erythematous patches or plaques gradually fade with residual hyperpigmentation (see Media Files 1-5). The center of the patch may blister or become necrotic. Other less common variants may manifest as lesions resembling erythema multiforme, toxic epidermal necrolysis, eczema, urticaria, a linear pattern following Blaschko lines, bullous lesions, a migrating eruption, or a nonpigmenting form with no postinflammatory hyperpigmentation.3 CausesThe major categories of causative agents of FDE include antibiotics, antiepileptics, nonsteroidal anti-inflammatory agents, and phenothiazines, although numerous other agents and certain foods have also been reported as causative agents. Ingestion of the causative agent may occur via any route, including oral, rectal, or intravenous.16
DIFFERENTIALSSection 4 of 11
WORKUPSection 5 of 11
Lab StudiesBlood studies are not useful for the diagnosis of FDE, although eosinophilia is common with drug eruptions. Other TestsPatch testing and oral provocation may be required to identify the suspected agent and check for cross-sensitivities to medications.17, 18 A refractory period has been reported in FDE; therefore, a delay before and between patch testing and oral provocation is recommended. One study used an 8-week time window after lesion resolution and between tests, which yielded positive results.19 Patch testing must be performed on a previously involved site; otherwise, a false-negative result is likely.18 Some locations may be inappropriate for patch testing; thus, clinical discretion is advised. Once patch testing is complete, oral provocation should follow, with the least likely culprits and the negative patch test agents first, followed by more likely causes. Oral provocation is thought to be the only reliable way to diagnose FDE. ProceduresSkin biopsy is the diagnostic procedure of choice. Histologic FindingsHistological examination of inflammatory/acute lesions shows an interface dermatitis with vacuolar change and Civatte bodies5 (see Media File 6). The overall pattern may mimic that seen in erythema multiforme. Dyskeratosis and individual necrotic keratinocytes within the epidermis may be a prominent feature (see Media File 7). On occasion, the lymphocytic infiltrate can be prominent enough to obscure the dermoepidermal junction. Spongiosis, dermal edema, eosinophils, and occasional neutrophils may be present. Pigmentary incontinence within the papillary dermis is a characteristic feature and may be the only feature seen in older, noninflamed lesions. Chronic or inactive lesions may also show mild acanthosis, hyperkeratosis, and relatively few inflammatory cells. TREATMENTSection 6 of 11
Medical CareThe main goal of treatment is to identify the causative agent and avoid it. Treatment otherwise is symptomatic. Systemic antihistamines and topical corticosteroids may be all that are required. In cases in which infection is suspected, antibiotics and proper wound care are advised. Desensitization to medications has been reported in the literature, but this should be avoided unless no substitutes exist.20 ConsultationsConsultation with a dermatologist is warranted if the diagnosis is in doubt. If patch testing is needed to determine which drug may be involved, a dermatologist with such experience may be required. If Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, hospitalization and possible referral to the intensive care unit or burn unit may be appropriate. DietA regular diet is usually acceptable. However, food may be an exacerbating factor; reactivation has been reported with lentils and strawberries.5 ActivityGenerally, no limits on activities are imposed. Multiple studies have sited male genital lesions occurring following intercourse with female partners taking trimethoprim-sulfamethoxazole.21 Therefore, patients may consider avoiding sexual activity while a partner is taking a medication that has resulted in a prior FDE. If open lesions are present, general wound care precautions are recommended. MEDICATIONSection 7 of 11
Lesions of FDE resolve spontaneously with avoidance of the inciting drug. Additional medications should be used to relieve symptoms associated with the condition. Generally, an oral antihistamine (eg, hydroxyzine) and a topical corticosteroid may be sufficient. The use of corticosteroids may interfere with later diagnostic provocation testing. Hyperpigmentation may take many months to resolve. Incontinent pigment in the dermis responds poorly to topical bleaching agents such as hydroquinones. FOLLOW-UPSection 8 of 11
Deterrence/PreventionAvoid the offending drug. Patch testing may be used to help identify agents that pose a risk of cross-sensitivity.22 ComplicationsHyperpigmentation is the most likely complication. The potential for infection exists in the setting of multiple, eroded lesions. Generalized eruptions have been reported following topical and oral provocation testing.16, 23 PrognosisThe prognosis is very good, and an uneventful recovery should be expected. No deaths due to FDE have been reported. Residual hyperpigmentation is very common, but this is less likely with the nonpigmenting variant. Patient EducationPatients should be counseled on medication avoidance and possible cross-reactions of similar medications. Patients should notify their physicians of all drug allergies they have experienced. MISCELLANEOUSSection 9 of 11
Medical/Legal PitfallsDrug reactions account for a large proportion of medical malpractice claims. Inadequate disclosure of potential adverse effects and failure to identify a drug as the cause of the patient's problem could be sources of legal action. MULTIMEDIASection 10 of 11
REFERENCESSection 11 of 11
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